Published online May 7, 2016. doi: 10.3748/wjg.v22.i17.4321
Peer-review started: January 10, 2016
First decision: January 28, 2016
Revised: February 10, 2016
Accepted: March 2, 2016
Article in press: March 2, 2016
Published online: May 7, 2016
AIM: To investigate whether the simultaneous treatment with human growth hormone (hGH) abolishes the negative effects of everolimus on anastomotic healing.
METHODS: Forty-eight male Sprague-Dawley-rats were randomized to three groups of 16 animals each (I: vehicle; II: everolimus 3 mg/kg po; III: everolimus 3 mg/kg po + hGH 2.5 mg/kg sc). Animals were pre-treated with hGH and/or everolimus daily for seven days. Then a standard anastomosis was created in the descending colon and treatment was continued for another seven days. The anastomosis was resected in toto and the bursting pressure was assessed as a mechanical parameter of intestinal healing. Moreover, biochemical (Hydroxyproline, PCNA, MPO, MMP-2 and MMP-9) and histological (cell density, angiogenesis, amount of granulation tissue) parameters of intestinal healing were assessed.
RESULTS: Anastomotic bursting pressure was significantly reduced by everolimus and a simultaneous treatment with hGH resulted in considerably higher values (I: 134 ± 19 mmHg, II: 85 ± 25 mmHg, III: 114 ± 25 mmHg; P < 0.05, I vs II; P = 0.09, I vs III and II vs III) Hydroxyproline concentration was significantly increased by hGH compared to everolimus alone (I: 14.9 ± 2.5 μg/mg, II: 8.9 ± 3.6 μg/mg, III: 11.9 ± 2.8 μg/mg; P < 0.05, I vs II/III and II vs III). The number of MPO-positive cells was reduced significantly by hGH compared to everolimus alone (I: 10 ± 1 n/mm², II: 15 ± 3 n/mm², III: 9 ± 2 n/mm²; P < 0.05, I vs II and II vs III), while the number of PCNA-positive cells were increased by hGH (I: 28 ± 3 /mm², II: 12 ± 3 /mm², III: 26 ± 12 /mm²; P < 0.05, I vs II and II vs III). Corresponding to these biochemical findings, HE-histology revealed significantly increased amount of granulation tissue in hGH-treated animals.
CONCLUSION: Inhibition of intestinal wound healing by everolimus is partially neutralized by simultaeous treatment with hGH. Both inflammation as well as collagen deposition is influenced by hGH.
Core tip: Patients undergoing transplantation are set onto immunosuppressive medication afterwards. One agent is everolimus out of the group of the mTOR-inhibitors. Everolimus has been shown to inhibit healing of intestinal anastomoses by influencing the inflammatory phase of wound healing. Human growth hormone (hGH) has been shown to improve wound healing by increasing the amount of collagen in the wound. In this animal study we could demonstrate for the first time that a combined perioperative treatment with everolimus and hGH results in improved intestinal wound healing compared with everolimus alone. These results might be a step towards safer immunosuppression in transplanted patients.